Advanced systems and methods for patient body temperature control

ABSTRACT

Devices, systems and methods for controlling the temperature of all or part of the body of a human or animal subject.

RELATED APPLICATION

This application is a continuation in part of copending U.S. patentapplication Ser. No. 15/594,539 entitled Advanced Systems and Methodsfor Patient Body Temperature Control filed May 12, 2017, the entiredisclosure of which is expressly incorporated herein by reference.

FIELD OF THE INVENTION

The present disclosure relates generally to the fields of medicine andengineering and more particularly to devices, systems and methods forcontrolling the temperature of a human or animal subject.

BACKGROUND

Pursuant to 37 CFR 1.71(e), this patent document contains material whichis subject to copyright protection and the owner of this patent documentreserves all copyright rights whatsoever.

Hypothermia can be induced in humans and some non-human animals for thepurpose of protecting various organs and tissues against the effects ofischemic, anoxic or toxic insult. Studies have shown that inducedhypothermia in a subject suffering from an evolving myocardialinfarction can, in at least some cases, limit the size and severity ofthe infarct. For example, in at least one study, it was observed thatpatients with anterior wall infarctions whose core body temperature hadbeen lowered to at least 35° C. prior to reperfusion by angioplasty hadsignificantly smaller median infarct size than other patients withanterior wall infarctions whose core body temperature was greater than35° C. at the time of reperfusion. This observation is not explained byother factors such as time-to-presentation, lesion location or quantityof antegrade coronary flow (TIMI Flow) prior to the angioplasty. Thiswould suggest that, at least in acute myocardial infarction (AMI) cases,lowering of the patient's core body temperature to at least 35° C. priorto reperfusion of the ischemic myocardium may have beneficial effects.

SUMMARY

Methods and systems for warming or cooling a subject, e.g., a targetlocation within a subject's vasculature, to a target temperature areprovided herein. A system may comprise at least one heat exchangeruseable to exchange heat with the subject's flowing blood at a heatexchange location different from the target location. Such method andsystem further comprises at least one temperature sensor positioned anduseable to sense body temperature(s) at one or more temperature sensinglocation(s) in or on the subject's body, such temperature sensinglocation(s) being different from the target location. Such method andsystem further comprises a controller which receives signals from thetemperature sensor(s) indicating the temperature being sensed at thetemperature sensing location(s) and, based on said signals, controls theheat exchanger to warm or cool blood flowing through the heat exchangelocation, as needed, to result in warming or cooling of the targetlocation and/or all or part of the subject to the target temperature.The controller may comprise a processor programmed to estimate thetemperature at the target location based on the temperature sensed atthe temperature sensing location. In some embodiments the controller mayalter the temperature sensed at the sensing location by adding orsubtracting a correction factor which is based on historical data or aknown expected temperature difference between the sensing location andthe target location. In other embodiments, the controller may beprogrammed to perform more complex operations and/or to apply algorithmswhich estimate the temperature at the target location, examples of whichare described herein. In some embodiments, the controller may estimatethe temperature at the target location in either current time or in realtime, based on the temperature sensed at the temperature sensinglocation at the current time or in real time, and based on the estimatedtemperature at the target location.

The temperature sensing location(s) may be at any suitable locations inor on the subject's body. Examples of useable temperature sensinglocations include locations in the inferior vena cava, superior venacava, pulmonary artery, renal vein and hepatic vein.

The methods and systems in certain embodiments may be used to effect acontrolled degree of therapeutic hypothermia, e.g., at a target location(e.g., the left ventricle of the heart) to deter or lessen damage froman insult (e.g., infarct, hypoxic insult, toxic insult, ischemic insult,etc.) at the target location or of the subject as a whole.

In accordance with one aspect of the present disclosure, there areprovided systems for warming or cooling a subject to a targettemperature comprising a heat exchanger configured to exchange heat withthe subject's flowing blood at a heat exchange location, a temperaturesensor configured to sense the temperature of the subject's blood at atemperature sensing location which may be within the subject'svasculature and a controller which comprises memory and a processor. Thecontroller is programmed to induce a plurality of periods of reducedheat exchange between the heat exchanger and the subject's flowingblood. The controller receives data representing sensed bloodtemperature during at least one of the plurality of reduced heatexchange periods. The controller uses the received data to provide anestimate of temperature at a target location in the subject. In anyembodiments disclosed herein, the estimate of temperature at the targetlocation may be calculated or provided on a repeating, serial,continual, continuous, running, rolling or any other suitable basis. Thetarget location may be the same as or close to the heat exchangelocation, or it may be elsewhere in the subject's body, such as in anorgan or other location that is upstream or downstream of thetemperature sensing location. The temperature sensing location and thetarget location may be the same location, or different locations. Thecontroller may be programmed to cause at least one of the reduced heatexchange periods to occur based on the estimate of temperature at thetarget location. The controller may be programmed to cause at least oneof the reduced heat exchange periods to occur based on a predeterminedchange in the estimate of temperature at the target location, such aswhen the estimate varies by a certain amount or when the estimatereaches a certain temperature or becomes within a certain range of thetarget temperature. The controller may be programmed to cause at leastone of the reduced heat exchange periods to occur when the runningestimate of temperature reaches or becomes equal to the targettemperature (i.e., a target-attainment reduced heat exchange period).The controller may be programmed to cause at least one of the reducedheat exchange periods to occur based on one or more elapsed timeperiods(s) after a prior reduced heat exchange period has occurred whenthe estimate of target temperature at the target location became equalto the target temperature. In some embodiments, the controller may beprogrammed to cause any possible combinations of time-based, estimatedtemperature-based, target attainment-based and/or post-target-attainmentbased reduced heat exchange periods. For example, the controller maycause at least one time-based reduced heat exchange period(s) to occurand, thereafter, the controller may cause at least one estimatedtemperature-based reduced heat exchange period(s) to occur based ondifference(s) between the estimate of temperature at the target locationand the target temperature, and, thereafter, the controller may cause atleast one estimated temperature-based reduced heat exchange p[period tooccur when the estimate of temperature becomes equal to the targettemperature and, thereafter, the controller may cause at least onetime-based heat exchange period to occur based on one or more elapsedtime periods after the estimated temperature-based reduced heat exchangeperiod that had occurred when the estimated temperature at the targetlocation became equal to the target temperature. The system may includea user interface by which a user may input the target temperature. Insome embodiments, heat exchange location may be within the subject'sinferior vena cava or superior vena cava, and the temperature sensinglocation may be in the subject's vasculature downstream of the heatexchange location. Examples of target locations may include a centralvenous location (e.g., right atrium) or a location within the leftventricle of the subject's heart. In some embodiments both the heatexchange location and the temperature sensing location may be in thesubject's inferior vena cava. In some embodiments, the controller mayadjust the heat exchange power of the heat exchanger. In someembodiments, the heat exchanger may be configured for circulation of aheat exchange fluid therethrough and the system may further comprises apump which pumps heat exchange fluid through the heat exchanger and thecontroller may be programmed to cause the reduced heat exchangeperiod(s) to occur by stopping or slowing the pump.

In accordance with another aspect of the present disclosure, there isprovided a system for warming or cooling a subject to a targettemperature, such system comprising; a heat exchange catheter having aheat exchanger through which a heat exchange fluid circulates, said heatexchange catheter being insertable into the subject's vasculature suchthat the heat exchanger exchanges heat with blood flowing through thesubject's vasculature at a heat exchange location; a temperature sensorconfigured to sense the temperature of the subject's blood at atemperature sensing location within the subject's vasculature; and acontroller which comprises memory and a processor, wherein thecontroller is programmed to alter the temperature and/or flow rate ofthe heat fluid so as to induce a plurality of periods of reduced heatexchange between the heat exchanger and the subject's flowing blood. Thecontroller may receive data representing sensed blood temperature duringat least one of the plurality of reduced heat exchange periods. Thecontroller may be programmed to use such received data to provide anestimate of temperature at a target location in the subject. Thecontroller may be programmed to cause at least one of the reduced heatexchange periods to occur based on the estimate of temperature at thetarget location. The temperature sensing location and the targetlocation may be the same location, or different locations. The reducedheat exchange periods may comprise any or all of time-based and/orestimated temperature-based and/or target attainment-based and/or posttarget attainment-based reduced heat exchange period(s), including allpossible combinations of any or all such reduced heat exchange periods.

Still further in accordance with the present disclosure, there isprovided a method comprising the steps of: providing a system whichcomprises a heat exchanger configured to exchange heat with thesubject's flowing blood, a temperature sensor and a controller;positioning the heat exchanger within the subject's vasculature suchthat the heat exchanger will exchange heat with the subject's blood at aheat exchange location; positioning the temperature sensor within thesubject's vasculature so as to sense the temperature of the subject'sblood at a temperature sensing location and causing the temperaturesensor to communicate, to the controller, data representing temperaturesensed at the temperature sensing location, wherein the controller usesreceived data representing temperature sensed at the temperature sensinglocation to calculate an estimate of temperature at a target location inthe subject and causes at least one reduced heat exchange period tooccur during performance of the method. During the reduced heat exchangeperiod(s), the controller recalculates at least one value used incalculating the estimate of temperature at the target location (e.g.,one or more constants or factors used to calculate the runningestimate). The reduced heat exchange periods may comprise any or all oftime-based and/or estimated temperature-based and/or targetattainment-based and/or post target attainment-based reduced heatexchange period(s), including all possible combinations of any or allsuch reduced heat exchange periods, including those summarized above. Insome embodiments the target location may be within the left ventricle ofthe subject's heart or central venous location of the subject and theheat exchange location may be within the subject's inferior or superiorvena cava and the temperature sensing location may be in the subject'svasculature upstream or downstream of the heat exchange location. Thetarget location may be in an organ or tissue wherein a zone of ischemia,infarct or abnormality exists and the method may be carried out toinduce hypothermia at the zone of ischemia, infarct or abnormality. Insome embodiments, the target location may be in an organ or tissue wherea reperfusion procedure is to be performed and the method may be carriedout to induce hypothermia in said organ or tissue prior to performanceof said reperfusion procedure.

Further aspects and details of the present invention will be understoodupon reading of the detailed description and examples set forthherebelow.

BRIEF DESCRIPTION OF THE DRAWINGS

The following detailed description and examples are provided for thepurpose of non-exhaustively describing some, but not necessarily all,examples or embodiments of the invention, and shall not limit the scopeof the invention in any way.

FIG. 1 shows an example of a heat exchange catheter system whichgenerally comprises a control console, tubing/cassette/sensor moduleassembly and heat exchange catheter, useable for practicing someembodiments described herein.

FIG. 2 is an exploded view of the control console with its access coverin an open position and the tubing/cassette/sensor module assemblystaged for insertion in, and operative connection to, the controlconsole.

FIG. 3 is a top (perspective) view of the control console with itsaccess cover in an open position and the tubing/cassette/sensor moduleassembly operatively inserted in and connected to the control console.

FIG. 4 is a right cross-sectional view of the control console.

FIG. 5 shows the heat exchange catheter of the system of FIG. 1.

FIG. 5A is a cross-sectional view through line 5A-5A of FIG. 5.

FIG. 5B is a cross-sectional view through line 5B-5B of FIG. 5.

FIGS. 6A through 6C show certain components of the endovascular heatexchange catheter embodiment of FIG. 2. Specifically, FIG. 6A is a sideview of the elongate member; FIG. 6B is a side view of the heat exchangetube and FIG. 6C is a side view of an optional elongate luminal memberand the distal tip member.

FIG. 7 shows an example of a system/method for controlling a subject'stemperature, including left ventricular temperature using anendovascular heat exchange catheter positioned at a heat exchangelocation in the subject's inferior vena cava and a temperature sensoradvanced through the heat exchange catheter and positioned at atemperature sensing location that is also in the subject's inferior venacava

FIG. 8 shows an example of a system/method for controlling a subject'stemperature, including left ventricular temperature using anendovascular heat exchange catheter positioned at a heat exchangelocation in the subject's inferior vena cava and a temperature sensoradvanced through the heat exchange catheter and positioned at atemperature sensing location in the subject's pulmonary artery.

FIG. 9 is an enlarged view of the distal portion of the temperaturesensor shown in FIG. 8.

FIG. 10 shows an example of a system/method for controlling a subject'stemperature, including left ventricular temperature using anendovascular heat exchange catheter positioned at a heat exchangelocation in the subject's inferior vena cava and a temperature sensorthat has been advanced via the superior vena cava to a temperaturesensing location in the subject's pulmonary artery.

FIG. 11 shows an example of a system/method for controlling a subject'stemperature, including left ventricular temperature using anendovascular heat exchange catheter positioned at a heat exchangelocation in the subject's inferior vena cava and a temperature sensoradvanced through the heat exchange catheter and positioned at atemperature sensing location in a hepatic vein of the subject.

FIG. 12 shows an example of a system/method for controlling a subject'stemperature, including left ventricular temperature using anendovascular heat exchange catheter positioned at a heat exchangelocation in the subject's inferior vena cava and a temperature sensoradvanced through the heat exchange catheter and positioned at atemperature sensing location in a renal vein of the subject.

FIG. 13 shows an example of a system/method for controlling a subject'stemperature, including left ventricular temperature using anendovascular heat exchange catheter positioned at a heat exchangelocation in the subject's inferior vena cava and a temperature sensorspositioned at temperature sensing locations in the inferior vena cavaand superior vena cava.

FIG. 14 is a graph of cooling time in pigs in accordance with theexample set forth below.

FIG. 15 is a graph showing a comparison of LV Estimate Error (i.e., thedifference between directly measured LV temperature and estimated LVtemperature) and IVC Error (i.e., the difference between directlymeasured LV temperature and directly measured IVC temperature) inaccordance with the example set forth below.

FIG. 16 shows an example of a Modify Therapy Screen which may appear onthe user interface of the system of FIG. 1.

FIG. 17 shows an example of an Operation Screen which may appear on theuser interface of the system of FIG. 1

FIG. 17A shows a pop-up menu which appears in response to pushing of the“Menu” icon on the screen shown in FIG. 17.

FIG. 18 shows a History Screen which may appear on the user interface ofthe system of FIG. 1.

FIG. 19 shows a Patient Temperature Screen which may appear on the userinterface of the system of FIG. 1

FIG. 20 shows an enlarged “zoom” view of a portion of the graphicdisplayed on the screen in FIG. 19.

FIG. 21 shows an Administration Screen which may appear on the userinterface of the system of FIG. 1

FIG. 22 shows a Settings Screen which may appear on the user interfaceof the system of FIG. 1.

FIG. 23 is a flow diagram showing one embodiment of a process for usinga heat exchange catheter system to deter reperfusion injury in a subjectwho is suffering from an ischemic event that is treatable by areperfusion procedure or administration of a reperfusion agent (e.g.,thrombolytic drug).

FIG. 24 is a diagram relating to a system wherein the controller isprogrammed to cause a combination of time-based and estimatedtemperature-based reduced heat exchange periods.

DETAILED DESCRIPTION

The following detailed description and the accompanying drawings towhich it refers are intended to describe some, but not necessarily all,examples or embodiments of the invention. The described embodiments areto be considered in all respects only as illustrative and notrestrictive. The contents of this detailed description and theaccompanying drawings do not limit the scope of the invention in anyway.

The drawings include showings of certain organs and other anatomicalstructures, which are labeled as follows:

-   -   Aorta . . . A    -   Heart . . . H    -   Right Atrium . . . RA    -   Left Atrium . . . LA    -   Right Ventricle . . . RV    -   Left Ventricle . . . LV    -   Pulmonary Artery . . . PA    -   Superior Vena Cava . . . IVC    -   Inferior Vena Cava . . . IVC    -   Femoral Vein . . . FV    -   Left Renal Vein . . . LRV    -   Right Renal Vein . . . RRV    -   Hepatic Veins . . . HV

FIG. 1 shows an example of a endovascular temperature management system10 which generally comprises an endovascular heat exchange catheter 12,an extracorporeal control console 14 and a tubing/cassette/sensor moduleassembly 60. Additionally, at least one body temperature sensor 16 isconnected by way of a temperature lead TL, or alternatively by wirelessconnectivity, to the controller 36. In the non-limiting example of FIG.1, the heat exchange catheter 12 has been inserted into the vasculatureof a subject and advanced to a position where its heat exchanger 18 isin the subject's inferior vena cava IVC. A temperature lead TL having atemperature sensor TS temperature sensor 16 is inserted through a lumenof the heat exchange catheter 12 and advanced out of the distal end ofthe catheter 12 to a temperature sensing location TSL that is also inthe subject's inferior vena cava IVC. As described elsewhere in thispatent application, in some embodiments, a plurality of temperaturesensors 16 may be employed.

The catheter 12, tubing/cassette/sensor module assembly 60 or cassetteassembly and temperature lead/sensor 16 may be disposable items intendedfor a single use, while the control console 14 may be a non-disposabledevice intended for multiple uses.

In the embodiment shown, the endovascular heat exchange catheter 12comprises an elongate catheter body which has a heat exchanger 18positioned thereon. Inflow and outflow lumens (not shown) are presentwithin the catheter body 16 to facilitate circulation of a thermalexchange fluid (e.g., sterile 0.9% sodium chloride solution or othersuitable thermal exchange fluid) through the heat exchanger 18.Optionally, the catheter may also include a working lumen (not shown inFIG. 1) which extends through the catheter body 16 and terminatesdistally at an opening in the distal end of the catheter body 16. Suchworking lumen may serve as a guidewire lumen to facilitate insertion andposition of the catheter 12 and/or may be used after insertion of thecatheter 12 for delivery of fluids, medicaments or other devices. Forexample, as shown in FIG. 1, in some embodiments, the temperature sensor16 may be inserted through the catheter's working lumen and advanced outof the distal end opening to a location beyond the distal end of thecatheter 12. Alternatively, in other embodiments, the temperature sensorTS may be positioned at various other locations on or in the subject'sbody to sense the desired body temperature(s).

The extracorporeal control console 14 generally comprises a main housing20 and a console head 24. As described in detail herebelow, the mainhousing 20 contains various apparatus and circuitry for warming/coolingthermal exchange fluid to controlled temperature(s) and for pumping suchwarmed or cooled thermal exchange fluid through the catheter 18 toeffectively modify and/or control the subject's body temperature. Theconsole head 24 comprises a display device or user interface 38, such asa touch screen system, whereby certain information may be input by, andcertain information may be displayed to, users of the system 10. On thehousing 20 there are provided a first connection port 40 for connectionof a temperature sensor TS that is inserted through the heat exchangecatheter 12 as shown in FIG. 1 as well as other connection ports 36, 38for connection of additional or alternative types of temperature sensorsand/or other apparatus.

As may be appreciated from the showing of FIG. 2, thetubing/cassette/sensor module assembly 60 generally comprises a sensormodule 34, an inflow conduit 32, inflow connector 33, outflow conduit30, outflow connector 31, temperature lead connector 40, pressure leadPL, cassette 64, cassette housing 62 and peristaltic pump tubing 65.

As shown in FIGS. 3 and 4, the cassette 64 of the tubing/cassette/sensormodule assembly 60 is inserted through an openable/closable access cover42 of the control console 14 and into a cassette receiving space 66positioned between thermal exchange plates 80 and the pump tubing 65 isinsertable into a tubing raceway 72 of pump 70.

With reference to FIG. 4, a thermal exchange engine 108 within thecontrol console 14 includes a refrigeration system for cooling fluidthat circulates through the thermal exchange plates 80 when the systemis operating in cooling mode and resistance heaters 82 for warming thethermal exchange plates 80 when the system is operating in warming mode.

The control console 14 also includes a programmable controller 36 anduser interface 24, such as a liquid crystal display (LCD), e.g.,touchscreen, which is in communication with the controller 36. The userinterface displays system information and also receives user input aswell as sensor data, as described more fully herein.

Further details of the control console 14, tubing/cassette/sensor moduleassembly 60 or cassette assembly and temperature lead TL/temperaturesensor 16 are described in copending U.S. patent application Ser. No.15/423,581 entitled Devices, Systems and Methods for EndovascularTemperature Control, the entire disclosure of which is hereby expresslyincorporated herein by reference.

With reference to FIGS. 5 through 6C, the heat exchange catheter 12 ofthe system shown in FIG. 1 generally comprises a proximal catheter body13 and an assembly which comprises the heat exchanger 18 attached toand/or extending distally from the proximal catheter body 13. In thisparticular embodiment, the proximal catheter body 13 has three lumens,an inflow lumen 15 a, an outflow lumen 15 b and an optional throughlumen 15 c. A hub 17 is mounted on the proximal end PE of the proximalcatheter body 13. The hub 17 has an inflow connector 30 that isconnected to the inflow lumen 15 a of the catheter body 13 and anoutflow connector 32 that is connected to the outflow lumen 15 b of theproximal catheter body 13. A through lumen port 22 on the hub 17 isconnected to the through lumen 15 c. The heat exchanger 18 of thiscatheter embodiment comprises at least first and second coiled heatexchange tube segments 300 a, 300 b. In some embodiments, additional(e.g., third, fourth) heat exchange tube segments may be used. The heatexchange tube segments 300 a, 300 b may be formed of any suitablematerial. In the particular example shown in FIGS. 1 through 3, the heatexchange tube segments 300 a, 300 b may be advantageously formed of anoncompliant polymeric material, such as polyethylene terephthalate(PET), Pebax, Polyolefin, Polyurethane and/or Nylon, or other suitablecompliant or noncompliant material and may be formed of a single tube orone or more tubes. In some embodiments the heat exchange tube segments30 a, 30 b may expand and collapse depending on whether or not they arefilled with fluid and, in such embodiments, the heat exchange tubesegments 30 a, 30 b may be referred to a “balloons.” For someapplications, the heat exchange tube segments 30 a and 30 b may haveouter diameters in the range of 2 mm-19 mm and wall thicknesses in therange of 0.0127 mm-0.1 mm.

In one example, the proximal end of the first tube segment 300 a isconnected to the inflow lumen 15 a and the proximal end of the secondtube 300 b segment is connected to the outflow lumen 15 b. The distalends of the first and second tube segments 300 a, 300 b are directly orindirectly in fluidic connection with each other such that heatexchanger fluid that has flowed in the distal direction through thefirst tube segment 300 a will then return in the proximal directionthrough the second tube segment 300 b. The distal ends of the heatexchange tube segment 33, 35 are connected to the inflow and outflowconnectors 30, 32 of the catheter 12. As seen in detail in FIGS. 6A-6C,the heat exchange assembly 301 may comprise a spine or elongate member400 and at least one heat exchange member 300 disposed on the spine orelongate member 400. This heat exchange assembly is attached to andextends distally from the proximal body 13, as shown. An introducersheath may be used to introduce the catheter into a patient's body.Alternatively, the catheter may be introduced without using anintroducer sheath.

The term “elongate member” may mean, in at least some embodiments, amember, e.g., a spine or similar structure, which extends from acatheter body and upon which at least one heat exchange member isdisposed. In at least some embodiments, the elongate member 400 isdistinguishable from the proximal body 13 on the basis of one or moredifferences in structure or physical property. In the particularembodiment shown, the elongate member 400 comprises an elongate,generally C-shaped member having receiving features 460 which comprisespaced-apart transverse notches, recesses or grooves formed along theopen side of the generally C-shaped member. The heat exchange member(s)300 may be inserted in these recessed, groove, or notch-type receivingfeatures 460 such that the helical loops extend around the closed sideof the generally C-shaped elongate member 400. The heat exchangemember(s) 300 may be secured to the receiving features 460 by adhesiveor other suitable means.

Non-limiting examples of other heat exchange catheters and relatedapparatus that may be used for some application are described in U.S.Pat. No. 9,492,633, and United States Patent Application PublicationsNos. 2013/0090708, 2013/0178923, 2013/0079855, 2013/0079856,2014/0094880, 2014/0094882, 2014/0094883, and unpublished, copendingU.S. patent application Ser. Nos. 15/395,858, 15/395,923 and 15/412,390,the entire disclosure of each such patent and application beingexpressly incorporated herein by reference. Other examples of cathetersthat may be used in this invention include those commercially availablefrom ZOLL Circulation, Inc., San Jose, Calif., such as the Cool Line®Catheter, Icy® Catheter, Quattro® Catheter, Solex 7® Catheter,InnerCool® RTx Accutrol Catheter and the InnerCool RTx StandardCatheter. Additionally incorporated herein by reference is the entiredisclosure of U.S. patent application Ser. No. 15/594,541 entitled,Devices, Systems and Methods for Endovascular Temperature Control filedon May 12, 2017.

In certain implementations, body temperature control systems and methodswherein the changes in temperature at target locations in a subject'sbody are estimated or indirectly determined without the need forpositioning a temperature sensor at such target location are providedherein.

FIG. 7 shows an example in which a heat exchange system, e.g., the heatexchange system 10 of FIG. 1, is used for controlling a temperature of apatient, e.g., at a Target Location TL within the left ventricle LV ofthe heart H. In this example, the heat exchange catheter 12 is insertedinto a femoral vein FV and advanced until its heat exchanger 18 is at aHeat Exchange Location HEL within the inferior vena cava IVC. Thetemperature sensor 16 has been advanced through a lumen of the heatexchange catheter 12 to a Temperature Sensing Location TSL within theinferior vena cava IVC downstream of the Heat Exchange Location HEL. Inthis example, the controller is programmed to use the temperature sensedby the sensor 16 at the Temperature Sensing Location TSL to estimate thetemperature at the Target Location TL within the left ventricle LV usingthe following algorithm:

TempLV=TempIVC+(K2−K1)·Power+L

wherein:

-   -   TempLV is the estimated temperature at the Target Location        within the left ventricle;    -   TempIVC is the current sensed temperature at the temperature        sensing location;    -   K1 is a constant which represents the change in TempLV per Watt        of heating or cooling power of the heat exchanger;    -   K2 is a constant which represents the change in TempIVC per Watt        of heating or cooling power;    -   Power is the power output of the heat exchanger; and    -   L is a constant which represents the expected change in the        temperature of blood as it circulates through the right heart        and lungs. The change in temperature may be due to environmental        factors such as the air temperature and humidity level inhaled        by the patient, and physiologic factors such as the efficiency        and capacity of the patient's lungs. In certain applications        and/or under certain conditions L may not be included in the        algorithm such that the algorithm would read        TempLV=TempIVC+(K2−K1)·Power. For example, the expected change        in the temperature of blood as it circulates through the right        heart and lungs may not be considered and/or may be assumed to        have minimal or no effect, e.g. on the LV.

The equation above is derived by considering the principle ofConservation of Energy applied to control volumes within the vasculatureof a patient being treated by a heat exchange device (e.g. a temperaturemanagement catheter). At least two control volumes within the body areof interest: first, a control volume around the temperature sensor whichis immediately downstream of the heat exchange device, second, a controlvolume around the target organ or tissue of interest. Based on energyconservation, the temperature rise of the control volume, when heat isapplied from the heat exchange device, can be described as: Bloodtemperature rise (delta T)=Power applied by the heat exchangedevice/(mass flow rate of blood perfusing the control volume*specificheat capacity of blood)*c, where c is an empirically derived constant. Aconstant K can be defined from the above equation as being equal toc/(mass flow rate of blood*specific heat capacity of blood), and can becomputed by measuring the above values, or alternately and preferably bymeasuring Blood delta T/Power.

The equation for K defined above can then be applied to the controlvolume of interest. K1 represents the Blood delta T as measured in thetarget organ or region under the influence of power from a heat exchangecatheter placed in the venous system of the body. For example, in thecase of AMI, the target organ or region would be the patient's leftventricle, as blood leaving this region flows into the coronary arterieswhich perfuse the myocardium. K2 represents the blood delta T measuredin a patient by a temperature sensor immediately downstream of a heatexchange catheter placed in the venous system of the body. For example,the heat exchange catheter could be placed in the patient's IVC.

In some embodiments, the controller 36 may be programmed with a fixedvalue for K1 that has been determined based on experimental orhistorical data. The experimental/historical data may be obtained fromsubjects who have undergone intravascular cooling and had a leftventricle (LV) temperature probe positioned in their left ventricle tomeasure LV blood temperature during cooling and during pump stops. Theobtained LV values are inserted into the formula below to obtain K1′ foreach pump stop for each subject. The average of the K1′ values is thencalculated to provide K1 (as per the formula below), which is used forfuture subjects to calculate an LV temperature where no LV temperatureprobe is present. For example, if the rise in LV temperature after apump stop was 0.75 C, and the power before the pump stop was 500 W, thenK1′ would be 0.0015. In the animal study cited in paragraphs 92-102below, a K1 value of 0.002 was used. This number was determined usingthe method described in this paragraph and the equation below, usingdata from prior animal studies.

${k\; 1^{\prime}} = ( \frac{{LV}_{{At}\mspace{14mu} X\mspace{14mu} {se}\; c\mspace{14mu} {into}\mspace{20mu} {pump}\mspace{14mu} {stp}} - {LV}_{{Before}\mspace{14mu} {pump}\mspace{14mu} {stop}}}{{Power}_{{Before}\mspace{14mu} {pump}\mspace{14mu} {stop}}} )$K 1 = average  (K 1^(′))

The controller 36 may be programmed to calculate K2 at each pump stopusing the formula below. For example, if the rise in IVC after a typicalpump stop was 3 C, and the power before the pump stop was 500 W, then K2would be 0.006.

${k\; 2} = \frac{{IVC}_{{At}\mspace{14mu} X\mspace{14mu} {se}\; c\mspace{14mu} {into}\mspace{14mu} {pump}\mspace{14mu} {stop}} - {IVC}_{{Before}\mspace{14mu} {pump}\mspace{14mu} {stop}}}{{Power}_{{Before}\mspace{14mu} {pump}\mspace{14mu} {stop}}}$

The value for L, in embodiments where L is utilized, may be stored inthe controller as a fixed value equal to the average change in bloodtemperature between the pulmonary artery PA and left ventricle LV basedon experimental or historical data.

The experimental/historical data used to determine L may be obtainedfrom subjects who have undergone intravascular cooling and had a leftventricle (LV) temperature probe positioned in their LV to measure LVblood temperature during cooling and during pump stops, and a pulmonaryartery (PA) temperature probe positioned in their PA to measure PA bloodtemperature during cooling and during pump stops. The obtained actualtemperature readings from the left ventricle (ActualTempLV) andpulmonary artery (ActualTempPA) are inserted into the equationActualTempLV±ActualTempPA=L′ to obtain L′ for each pump stop for eachsubject. The average of the L′ values_is then calculated to provide a Lfor use by the controller in calculating estimated LV temperature(TempLV) for future subjects in whom a PA temperature probe is presentbut in whom no LV temperature probe is present, using the formulaTempLV=ActualTempPA±L.

To measure Power, the system 10 may be equipped with additionaltemperature sensors for determining the temperature of heat exchangefluid flowing to the heat exchanger 18 and the temperature of heatexchange fluid flowing from the heat exchanger 18. Such measurements ofthe heat exchange fluid temperature may be used by the controller 36 tocompute the Power output of the heat exchanger 18. Specifically,controller 36 may be programmed to use those measurements of the heatexchange fluid temperature to periodically or continually calculate thevalue for Power using the following formula:

Power(Watts)=(HE Fluid Temp OUT−HE Fluid Temp IN)·Flow Rate of HEFluid·CP

wherein:

-   -   HE Fluid Temp IN is the current measured temperature of heat        exchange fluid flowing into the heat exchanger;    -   HE Fluid Temp OUT is the current measured temperature of heat        exchange fluid flowing out of the heat exchanger;    -   Flow Rate is the measured or calculated volumetric flow rate of        heat exchange fluid through the heat exchanger; and    -   CP is the specific heat capacity of the heat exchange fluid.    -   E.g., volumetric flow rate may be detected using a flow sensor        or in a system that uses a roller pump, volumetric flow rate may        be equal to the pump rotational speed multiplied by a constant        proportional to the cross sectional area and length of tubing        within the pump.

In at least some applications, the heat exchange fluid will be 0.9% NaClsolution, the CP value for which is 4.2 Joules per degree Celsius.

In other embodiments, the controller 36 may be programmed to calculate aK1 at each pump stop using, for example, the following formula:

K1=K2·averageCK ratio

-   -   wherein averageCK ratio is the ratio of K1 to K2 determined on        the basis of experimental or historical data.

The experimental/historical data used to determine averageCK ratio maybe obtained from subjects who have undergone intravascular cooling andhad a left ventricle (LV) temperature probe positioned in their LV tomeasure LV blood temperature during cooling and during pump stops, andan inferior vena cava (IVC) temperature probe positioned in their IVC tomeasure IVC blood temperature during cooling and during pump stops. Foreach pump stop in the data set, the obtained LV values are inserted intothe formula below to obtain K1′.

${k\; 1^{\prime}} = ( \frac{{LV}_{{At}\mspace{14mu} X\mspace{14mu} {se}\; c\mspace{14mu} {into}\mspace{20mu} {pump}\mspace{14mu} {stop}} - {LV}_{{Before}\mspace{14mu} {pump}\mspace{14mu} {stop}}}{{Power}_{{Before}\mspace{14mu} {pump}\mspace{14mu} {stop}}} )$

For each pump stop in the data set, the obtained IVC values are insertedinto the formula below to obtain K2

${k\; 2} = \frac{{IVC}_{{At}\mspace{14mu} X\mspace{14mu} {se}\; c\mspace{14mu} {into}\mspace{14mu} {pump}\mspace{14mu} {stop}} - {IVC}_{{Before}\mspace{14mu} {pump}\mspace{14mu} {stop}}}{{Power}_{{Before}\mspace{14mu} {pump}\mspace{14mu} {stop}}}$

For each pump stop in the data set, K1′ and K2 are inserted into theequation CK ratio=K1′/K2 to calculate the CK ratio for each pump stopfor each subject. For example, if the K1 was 0.0015 and the K2 was0.006, then the CKratio would be 0.25. The CK ratios for all pump stopsfor all subjects are then averaged to provide averageCK ratio for use incalculating K1 using the formula K1=K2·averageCK ratio for futuresubjects where no LV temperature probe is present.

In other embodiments, LV_(Before pump stop) can be calculated based on aregression model and a new k1′ value can be determined at every pumpstop. LV_(Before pump stop) is known to be dependent onLV_(At X sec into pump stop) as well as Power_(Before pump stop).Therefore, a regression analysis can be used to develop a relationshipusing existing preclinical data.

Based on multiple linear regression, the following relationship may beobtained:

LV_(Before pump stop)=a0+(a1*LV_(At X sec into pump stop))+(a2*Power_(Before pump stop))

Where a0=−2.4691, a1=1.0674, a2=−0.03. Based on this equation a new k1′value can be determined at every pump stop following the equation

${k\; 1^{\prime}} = ( \frac{{LV}_{{At}\mspace{14mu} X\mspace{14mu} {se}\; c\mspace{14mu} {into}\mspace{20mu} {pump}\mspace{14mu} {stop}} - {LV}_{{Before}\mspace{14mu} {pump}\mspace{14mu} {stop}}}{{Power}_{{Before}\mspace{14mu} {pump}\mspace{14mu} {stop}}} )$

This can then in turn be used in the above equation to calculate theestimated temperature at the Target Location within the left ventricle.

In some embodiments where the pump 34 is stopped periodically oroccasionally and K1 is a fixed value based on experimental or historicaldata (as discussed herein), the controller may be programmed to applythe above-described algorithms for ongoing recalculation of K2 by aprocess that comprises the following steps:

-   -   calculating and recording Power before a pump stop;    -   recording the temperature at the Temperature Sensing Location        (e.g., the IVC temperature) before pump stop;    -   effecting pump stop;    -   recording the temperature at the Temperature Sensing Location        (e.g., the IVC temperature) at x seconds into said pump stop;    -   calculating a new K2 value if the Power recorded before said        pump stop is greater than a predetermined threshold value; and    -   applying the new K2 value, if calculated, for subsequent LV        calculation.

As shown above, calculation of K2 requires computation of a quotientcontaining the factor “Power before pump stop” in the denominator. Ifthis factor is exactly equal to zero, and the numerator is non-zero, thecalculated K2 becomes infinite. Having an infinite K2 causes thecalculation for TempLV to become infinite for non-zero power levels,which is not useful. In principle, if the denominator of the K2 equation(Power before a pump stop) becomes zero, the numerator (IVC x sec intopump stop—IVC before pump stop) would also be expected to become zero.That is, if there is no measured power, there should be no change in IVCtemperature. This would result in a calculation of 0/0, which ismathematically indeterminate, and is not a usable result as calculationof TempLV could not be completed. Similarly, if the numerator anddenominator of the K2 calculation are both near zero, the results arefinite but highly uncertain, as small measurement errors will have alarge effect on the resulting K2. For example, if the rise in IVC aftera typical pump stop was 3 C, and the power before the pump stop was 500W (K2 would be 0.006), and the power measurement was in error by +10Watts, K2 would have an error of +2% which is acceptable. However if IVCtemperature rise and power were very small, (for example, 0.12 C, and 20W) and the same error was present (+10 W), the calculation would be inerror by 100%. Whereas in the previous situations computation could notbe completed, this scenario presents more risk to the patient as asensible K2 is computed but is in fact erroneous and will lead tounacceptable estimates for TempLV. To avoid this scenario, the algorithmshould avoid calculating K2 when catheter power before a pump stop isbelow a predetermined threshold. The value of this threshold depends onthe accuracy of the IVC temperature reading, and the accuracy of thecatheter power calculation. The power calculation is in turn dependenton the accuracy of the catheter inlet and outlet temperaturemeasurements, and the accuracy of the catheter flow rate measurement. Inpractice this threshold is in the range of 10 to 60 Watts, e.g., 30Watts.

In some embodiments where the pump 17 is stopped periodically oroccasionally and both K1 and K2 are recalculated at each pump stop, thecontroller 36 may be programmed to apply the above-described algorithmsfor ongoing recalculation of K1 and K2 by a process that comprises thefollowing steps:

-   -   calculating and recording Power before a pump stop;    -   recording temperature at the Temperature Sensing Location (e.g.,        the IVC temperature) before said pump stop;    -   effecting the pump stop;    -   recording temperature at the Temperature Sensing Location (e.g.,        the IVC temperature) at x seconds into said pump stop;    -   if the Power recorded before said pump stop is greater than a        predetermined threshold value, calculating new K1 and K2 values,        and    -   applying the new K1 and K2 values, if calculated, for subsequent        LV calculation.

In some embodiments, the calculation of K1 and/or K2 may be based onrunning average, median or filtered value. In such embodiments, thecontroller 36 may, for example, be programmed to apply theabove-described algorithms by a process that comprises the followingsteps:

-   -   calculating and recording Power before a pump stop;    -   recording temperature at the Temperature Sensing Location (e.g.,        the IVC temperature) before the pump stop;    -   effecting said pump stop;    -   recording temperature at the Temperature Sensing Location (e.g.,        the IVC temperature) at x seconds into said pump stop;    -   if the Power recorded before said pump stop is greater than a        predetermined threshold value, calculating a new K2 value; and    -   if a new K2 value has been calculated, calculating a running        average, median or filtered K2 value based on the new K2 value        and one or more previous K2 values and, thereafter, using said        running average, median or filtered K2 value for LV calculation.

FIG. 8 shows another example of a system/method for controllingtemperature at a Target Location TL in the left ventricle LV using anendovascular heat exchange catheter 12 positioned at a Heat ExchangeLocation HEL in the subject's inferior vena cava IVC (e.g., via femoralaccess) and a temperature sensor 16 positioned at a Temperature SensingLocation in the subject's pulmonary artery PA. In this particularexample, the temperature sensor 16 has been advanced through the heatexchange catheter 12 and into the pulmonary artery PA. However,temperature sensors may be placed in the pulmonary artery PA by numerousother means, some examples of which are discussed below. In someembodiments, the temperature sensor in the PA may be placed viainsertion through the internal jugular (IJ) or subclavian vein (SV).

The temperature of mixed venous blood flowing through the pulmonaryartery PA is typically within about 0.5 degrees C. of the temperature inthe left ventricle, e.g., between 0.02 and 0.07 degrees C. This is basedon pig experiments where a temperature probe was placed in the rightventricle of a pig, immediately upstream of the pulmonary artery, and asecond temperature probe was placed in the left ventricle. Thedifference between the temperature in the pulmonary artery PA and thatin the Left Ventricle LV is due to the gain or loss of heat as the bloodcirculates through the lungs, i.e., the above defined “lung constant”(L). In some applications where a coarse approximation of leftventricular temperature is acceptable, the measured temperature in thepulmonary artery PA may be used, either without modification or aftersubtraction of a predetermined correction factor or L intended toaccount approximately for the lung effect (e.g., −0.1° C., −0.2° C.,−0.3° C., −0.5° C., etc.), as a surrogate for the left ventriculartemperature. In other applications, the controller 36 may be programmedto calculate the estimated left ventricular temperature using thefollowing formula:

TempLV=PA±L

-   -   wherein:    -   TempLV means estimated left ventricular temperature;    -   PA means sensed pulmonary artery temperature; and    -   L is a constant which represents the expected change in        temperature of blood as it circulates through the right heart        and lungs, which may be determined or estimated as described        above.

With particular reference to FIG. 9, the temperature sensor 16 maycomprise an elongate, flexible shaft such as a wire or catheter havingone or more temperature measuring devices (e.g., thermistor(s)) thereonor therein to measure temperature at the desired Temperature SensingLocation. Optionally, to facilitate flow-directed advancement of thetemperature sensor 16 into the pulmonary artery PA, an inflatableballoon or other buoyant member 17 may also be provided on the elongateshaft. Flow-directed placement of a pulmonary artery catheter using aballoon is a technique well known in the art. Also, optionally, one ormore additional port(s) and/or port(s) and/or sensor(s) 17 may bepositioned on the elongate shaft for monitoring additional variables orparameters within the pulmonary artery (e.g., pulmonary artery pressure,pulmonary artery wedge pressure, pulmonary artery flow rate, continuouscardiac output, etc.).

FIG. 10 shows another non-limiting example in which the heat exchangecatheter 12 is advanced into the subject's inferior vena cava IVC andits heat exchanger 18 is positioned at a Heat Exchange Location HEL inthe inferior vena cava IVC and a separate temperature sensor 16 isadvanced to a Temperature Sensing Location in the pulmonary artery PA.In this manner, the temperature at the Target Location TL in the leftventricle LV may be determined in the same manner as described above inrelation to FIG. 3, but in this approach the temperature sensor 16 isnot advanced through the heat exchange catheter 12. As described above,the temperature sensor 16 shown in FIG. 5 may optionally be equippedwith a balloon 17 and/or port(s) and/or sensor(s) 17 for monitoringadditional variables or parameters within the pulmonary artery PA. Insome cases, the pulmonary temperature sensor 16 may be incorporated in apulmonary artery catheter, such as a Swan-Gantz catheter, having otherfunctions for hemodynamic monitoring in addition to the temperaturesensor.

In the example of FIG. 11, the heat exchange catheter 12 is advancedinto the subject's inferior vena cava IVC and its heat exchanger 18 ispositioned at a Heat Exchange Location HEL in the inferior vena cavaIVC. The temperature sensor is advanced through a lumen of the heatexchange catheter and to a Temperature Sensing Location within a hepaticvein HV. In this embodiment, the controller 36 may be programmed tocalculate estimated temperature at the Target Location in the leftventricle LV using the following formula:

TempLV=HV±K _(hepatic)

-   -   wherein:    -   TempLV means estimated left ventricular temperature;    -   HV means sensed hepatic vein temperature; and    -   K_(hepatic) is a constant which represents the expected change        in temperature of blood as it circulates through the subject's        liver

In the embodiment of FIG. 11, the controller 36 may be pre-programmedwith a value for K_(hepatic) based on previous experimental orhistorical data. The experimental/historical data used to determineK_(hepatic) may be obtained from subjects who have undergoneintravascular cooling and had a left ventricle (LV) temperature probepositioned in their actual left ventricle (ActualTempLV) to measure leftventricular blood temperature during cooling and during pump stops, anda hepatic vein (HV) temperature probe positioned in their HV to measureHV blood temperature during cooling and during pump stops. The obtainedActualTempLV values and HV values are inserted into the equationActualTempLV±HV=K′_(hepatic)′ to obtain K′_(hepatic) for each pump stopfor each subject. The average of the K′_(hepatic) values is thencalculated to provide K_(hepatic) for use by the controller incalculating estimated left ventricular temperature (TemoLV) in futuresubjects where no LV temperature probe is present, using the formulaTempLV=HV±_K_(hepatic).

FIG. 12 shows an example that is similar to the approach used in FIG.11, but wherein the temperature sensor 16 is advanced to a TemperatureSensing Location within the left renal vein LRV. The right renal veinRRV may be used as an alternative. In this example, the controller 36may be programmed to calculate estimated temperature at the TargetLocation in the left ventricle LV using the following formula:

TempLV=RV±K _(kidney)

-   -   wherein:    -   TempLV means estimated left ventricular temperature;    -   RV means sensed renal vein temperature; and    -   K_(kidney) is a constant which represents the expected change in        temperature of blood as it circulates through the subject's        kidney.

In the embodiment of FIG. 11, the controller 36 may be pre-programmedwith a value for K_(Kidney) based on previous experimental or historicaldata. The experimental/historical data used to determine K_(kidney) maybe obtained from subjects who have undergone intravascular cooling andhad a left ventricle (LV) temperature probe positioned in their LV tomeasure the actual left ventricular blood temperature (ActualTempLV)during cooling and during pump stops, and a renal vein (RV) temperatureprobe positioned in their RV to measure RV blood temperature duringcooling and during pump stops. The obtained ActualTempLV values and RVvalues are inserted into the equation ActualTempLV±RV=K′_(kidney) toobtain K′_(kidney) for each pump stop for each subject. The K′_(kidney)for all subjects are then averaged to provide a K_(kidney) for use bythe controller in calculating estimated LV temperature (TempLV) forfuture subjects where no LV temperature probe is present, using theformula TempLV=RV±K_(kidney).

FIG. 13 shows an example in which two temperature sensors 16 a, 16 b areused. In this example, the endovascular heat exchange catheter 12 isadvanced into the inferior vena cava (e.g., via femoral access) suchthat its heat exchanger 18 is positioned at a Heat Exchange Location HELin the subject's inferior vena cava IVC. An elongate temperature probecomprising the temperature sensors 16 a, 16 b is advanced through theheat exchange catheter and to a position where the first temperaturesensor 16 a is at a Temperature Sensing Location in the inferior venacava and the second temperature sensor 16 b is at a Temperature SensingLocation in the superior vena cava SVC. In alternative embodiments, thetemperature sensor in the SVC may be placed via insertion through theinternal jugular (IJ) or subclavian vein (SV). In this example, thecontroller 36 may be programmed to calculate the estimated temperatureat a Target Location in the left ventricle LV (TempLV) using thefollowing formula:

TempLV=(SVC·1/r+1)+(IVC·r/r+1)±L

-   -   wherein:    -   TempLV means estimated left ventricular temperature;    -   SVC means sensed superior vena cava temperature; IVC means        sensed inferior vena cava temperature;    -   r means ratio of SVC flow rate to IVC flow rate; and    -   L is a constant which represents the expected change in the        temperature of blood as it circulates through the right heart        and lungs, which may be determined in the manner discussed        above.

The controller 36 may be pre-programmed with a value for r based onprevious experimental or historical data. The experimental/historicaldata used to determine r may be obtained from subjects who haveundergone intravascular cooling and had a left ventricle (LV)temperature probe positioned in their LV to measure actual LV bloodtemperature (ActualTempLV) during cooling and during pump stops, and aSVC flow sensor positioned in their SVC to measure SVC blood flow rateduring cooling and during pump stops and an IVC flow sensor positionedin their IVC to measure IVC blood flow rate during cooling and duringpump stops. The SVC blood flow rate and the IVC blood flow rate for allsubjects are then averaged and the ratio of the average SVC blood flowrate and average IVC blood flow rate=r, which is used by the controllerin calculating estimated LV temperature (TempLV) for future subjectswhere no LV temperature probe is present, using the formulaTempLV=(SVC·1/r+1)+(IVC·r/r+1)±L.

In other embodiments, the heat exchange catheter may be advanced intothe subject's inferior vena cava IVC (e.g., via femoral access) and itsheat exchanger is positioned at a Heat Exchange Location HEL in theinferior vena cava IVC. A temperature sensor may positioned in aTemperature Sensing Location within one or more of the right or leftinternal jugular veins (IJ), the right or left subclavian veins, theright or left innominate veins or the superior vena cave (SVC).Temperature offsets may be determined for each of these locations: theupper body (SVC or innominate vein); the arm (subclavian); the head(internal jugular) In certain embodiments, the controller may beprogrammed to calculate estimated temperature at the Target Location inthe left ventricle LV using the following formulas:

TempLV=SVC or Innominate±K _(upper body)

TempLV=subclavian±K _(subclavian)

TempLV=jugular±K _(jugular)

-   -   wherein:    -   TempLV means estimated left ventricular temperature;    -   SVC or Innominate means sensed SVC or Innominate vein        temperature; Subclavian means sensed subclavian vein        temperature; jugular means sensed internal jugular vein        temperature; and    -   K_(upper body) is a constant which represents the expected        change in temperature of blood as it circulates through the        subject's upper body (SVC or innominate vein), K_(subclavian) is        a constant which represents the expected change in temperature        of blood as it circulates through the subject's subclavian vein,        K_(jugular) is a constant which represents the expected change        in temperature of blood as it circulates through the subject's        internal jugular vein.

A controller may be pre-programmed with a value for K_(upper body),K_(subclavian), or K_(jugular) based on previous experimental orhistorical data. The experimental/historical data used to determinethese values may be obtained from subjects who have undergoneintravascular cooling and had a left ventricle (LV) temperature probepositioned in their LV to measure actual LV blood temperature(ActualTempLV) during cooling and during pump stops, and an SVC,innominate, subclavian, or internal jugular temperature probe positionedin their SVC, innominate, subclavian, or internal jugular to measureSVC, innominate, subclavian, or internal jugular blood temperatureduring cooling and during pump stops. For example, the obtainedActualTempLV values and SVC values are inserted into the equationActualTempLV±SVC=K′_(upper body) to obtain K′_(upper body) for eachsubject. The K′_(upper body) for all pump stops for all subjects arethen averaged to provide a K_(upper body) for use by the controller incalculating estimated left ventricular temperature (TempLV) temperaturefor future subjects where no LV temperature probe is present, using theformula TempLV=SVC±K_(upper body). These steps can be performed for theinnominate, subclavian or internal jugular values as well, using theirrespective equations (above).

In certain embodiments, the duration of a pump stop may be reduced bydraining or reducing the capacitance in the tubing (e.g., in the inflowline connecting the console (e.g., via a cassette within the console) tothe catheter) through which the heat exchange fluid flows, more quickly.As a result, it would take less time for the heat exchange fluid flow tostop after a pump stop, thereby reducing the temperature decay time ofthe catheter. This may be accomplished by running the pump backwardsuntil the cassette pressure sensor reads >5 psi. For example, using thismethod, it would take about 7 seconds for heat exchange fluid flowing ata rate of about 410 ml/min to stop flowing.

Other implementations of body temperature control systems and methodswherein the changes in temperature at target locations in a subject'sbody are estimated or indirectly determined without the need forpositioning a temperature sensor at such target location are describedherein.

In another embodiment, a system for warming or cooling a target organ oranatomical region within a subject's vasculature to a target temperaturemay include a heat exchanger. The heat exchanger may be configured toexchange heat with the subject's flowing blood at a heat exchangelocation. The system may include a first temperature sensor, whichsensor can sense the temperature of the subject's flowing blood at atemperature sensing location. The first temperature sensor may bepositioned downstream from the heat exchanger relative to a direction ofthe flowing blood. The system also includes a controller. The controllermay receive signals from the temperature sensor indicative of the bloodtemperature being sensed at the temperature sensing location. Thecontroller includes a processor programmed to estimate the temperatureat the target organ or anatomical region. The temperature is estimatedbased on the following: the temperature sensed at the temperaturesensing location; a heat capacity of at least one intervening organ oranatomical region between the temperature sensing location and thetarget organ or anatomical region; and a power output of the heatexchanger. Relative to the direction of the flowing blood, theintervening organ or anatomical region is located downstream from thefirst temperature sensor, and the target organ or anatomical region islocated downstream from the intervening organ or anatomical region.Based on the estimated temperature at the target organ or anatomicalregion, the controller can control the heat exchanger to warm or coolblood flowing through the heat exchange location as needed to result inwarming or cooling of the target organ or anatomical region to thetarget temperature.

In certain embodiments, the heat capacity of at least one interveningorgan or anatomical region between the temperature sensing location andthe target organ or anatomical region may be predetermined and/orestimated.

For example, the processor may be programmed to estimate the temperatureat the target organ or anatomical region based on the heat capacities ofat least two intervening organs or anatomical regions between thetemperature sensing location and the target location. The heat capacityof a first intervening organ or anatomical region is predetermined,while the heat capacity of a second intervening organ or anatomicalregion is estimated.

In other embodiments, the heat capacity of at least one interveningorgan or anatomical region between the temperature sensing location andthe target organ or anatomical region may be represented by apredetermined constant based on historical experimental temperature dataof the intervening organ or anatomical region.

The system may include a pump for pumping a heat exchange fluid throughthe heat exchanger to exchange heat with the subject's flowing blood.The pumping of said heat exchange fluid through the heat exchanger maybe stopped periodically or occasionally and the heat capacity of atleast one intervening organ or anatomical region between the temperaturesensing location and the target organ or anatomical region may beestimated or otherwise calculated at each pump stop.

In certain embodiments, where the temperature of the left ventricle isestimated and the heat exchanger is positioned in the inferior venacava, at least one intervening organ or anatomical region between thetemperature sensing location and the target organ or anatomical regionmay include at least a portion of the inferior vena cava and the leftventricle.

In certain embodiments, the system may include a first and secondtemperature sensor. The first temperature sensor may be located distalto the heat exchanger and the second temperature sensor may be locatedproximal to the heat exchanger. The heat capacity of at least oneintervening organ or anatomical region between the temperature sensinglocation and the target organ or anatomical region may be estimatedwithout a pump stop or with a pump stop having a reduced duration bycalculating the difference between the temperature sensed by the firstsensor and the temperature sensed by the second sensor, and utilizingthat difference in the estimation or calculation of the heat capacity ofat least one intervening organ or anatomical region between thetemperature sensing location and the target organ or anatomical region.In certain embodiments, the first and second temperature sensors may belocated is the inferior vena cava, or in any other region of the body,depending on the location of the target organ or anatomical region. Forexample, the target organ or anatomical region may include the leftventricle, brain, kidney or liver.

In certain embodiments, the system may include first temperature sensorlocated distal to a heat exchanger. The first temperature sensor may beposited in the inferior vena cave and a second temperature sensor may bepositioned in the esophagus, such that the heat capacity of an organ oranatomical region near the esophagus can be estimated.

In certain embodiments, the system may include first temperature sensorlocated distal to a heat exchanger. The first temperature sensor may beposited in the inferior vena cave and a second temperature sensor may bepositioned in the pulmonary artery, such that the heat capacity of anorgan or anatomical region near the pulmonary artery can be estimated.

In other embodiments, the heat capacity of at least one interveningorgan or anatomical region between the temperature sensing location andthe target organ or anatomical region may be estimated and/or adjustedbased on one or more patient parameters, e.g., weight, girth, and musclemass.

In certain embodiments, any of the above describes systems may beutilized where the target organ or anatomical region is within the leftventricle of the subject's heart, the heat exchange location is withinthe subject's inferior vena cava or superior vena cava, and thetemperature sensing location is in the subject's vasculature downstreamof the heat exchange location. Optionally, both the heat exchangelocation and the temperature sensing location may be in the subject'sinferior vena cava. The system controller may adjust the power of theheat exchanger based on an estimated temperature at the target organ oranatomical region.

In one example, a system may include a controller programmed to estimatetemperature at the target location within the left ventricle (TempLV)using the algorithm:

TempLV=IVC+Power(K2−K1+K _(LUNG)):

TempLV=is the estimated temperature at the target location within theleft ventricle;

IVC=is the current sensed temperature at the temperature sensinglocation;

K1=is a constant which represents the change in LV Temperature per Wattof eating or cooling power of the heat exchanger;

K2=is a constant which represents the change in IVC temperature per Wattof heating or cooling power;

Power=is the power output of the heat exchanger; and

K_(LUNG)=is a constant which represents the change in the temperature ofblood as it circulates through the right heart and lungs per Watt ofheating or cooling power of the heat exchanger

In certain embodiments, K1, K2, and Klung are inversely proportional tospecific heat capacity, where the units of K1, K2 and Klung are indegrees Celsius/Watt, which is the inverse of the standard definition ofheat capacity, which is J/degrees Celsius. Furthermore, as mentionedabove, K1 K2 may be defined as being equal to c/(mass flow rate ofblood*specific heat capacity of blood). K1, K2 and Klung may also bethought of as representing a form of heat responsiveness, or alternatelyheat capacity, in the sense that they represent the organ's oranatomical region's responsiveness to heat.

Estimation of Left Ventricular Temperature in Anesthetized Swine

Applicant has confirmed the accuracy and feasibility of one embodimentof the present invention in animals. Eight (8) adult swine having bodyweights ranging from 42 kg to 101 kg were anesthetized with isoflurane,intubated and placed on mechanical ventilation. Data from one animal wasexcluded from this analysis due to hardware issues encountered duringtesting. In each animal, a Triton™ endovascular heat exchange catheter(ZOLL Circulation, Inc., San Jose, Calif.) was inserted into the femoralvein and advanced to a position within the inferior vena cava. Specificsof the Triton™ endovascular heat exchange catheter are described in U.S.patent application Ser. No. 15/395,858 entitled Fluid-CirculatingCatheters Useable for Endovascular Heat Exchange, the entire disclosureof which is expressly incorporated herein by reference. Also, the heatexchange catheter used in this example is shown in FIGS. 5 through 6C ofthis patent application and summarized above. A Triton endovasculartemperature probe (“IVC Probe”) was inserted through the working lumenof the heat exchange catheter and advanced to a position within theinferior vena cava approximately 2 cm downstream of the heat exchangecatheter's heat exchanger. A temperature probe (“LV Control Probe”) wasalso placed in the left ventricle to directly monitor the actualtemperature within the left ventricle. Three (3) additional probes(“Extracardiac Control Probes”) were also placed in each animal, withinthe SVC, aorta, and contralateral iliac vein to document the occurrenceof any temperature related adverse events. All temperature probes wereconnected to the AD instruments Power lab 16/30 DAQ system and the datawas recorded. The heat exchange catheter and the IVC Temperature Probewere also connected to a Thermogard XP3 System Console (ZOLLCirculation, Inc., San Jose, Calif.), particulars of which are describedin U.S. patent application Ser. No. 15/423,581 entitled Devices, Systemsand Methods for Endovascular Temperature Control, the entire disclosureof which is expressly incorporated herein by reference. Also, the systemconsole and related disposables used in this example are shown in FIGS.1 through 4 of this patent application and summarized above.

In this experiment, the Temperature Sensing Location L is the inferiorvena cava (IVC Probe) and the Target Location TL is the left ventricleLV, as generally shown in FIG. 1. The controller of a system describedherein, e.g., the Thermogard XP3 System Console, is programmed to causethe Console's pump to perform pump stops and to use the temperaturesensed by the IVC Probe as the Temperature Sensing Location TSL and toestimate the temperature at the Target Location TL within the leftventricle LV using the algorithm (TempLV=TempIVC+(K2−K1)·Power) andprocedure described above. Alternatively, TempLV=TempIVC+(K2−K1)·Power+Lcould be used. Pump stops occurred as follows:

Pump Stop Number Timing of Pump Stop 1 90 seconds after commencement ofcooling 2 When the estimated LV temperature has been lowered to 1.5degrees C. above the target temperature (i.e., at 33.5 degrees C.) 3When the estimated LV temperature has been lowered to the targettemperature (i.e., at 32.0 degrees C.) 4 through 8 Every 10 minutes

FIG. 14 shows the time it took for the system to cool each animal'sestimated left ventricular temperature to 34 degrees C. and 32 degreesC., respectively. As seen in FIG. 14, the system cooled all eightanimals from normothermia to 34 degrees C. in less than 6 minutes. Thetime required to reach the target temperature of 32 degrees was morevariable and ranged from less than 6 minutes to just under 24 minutes.However, all eight pigs were cooled to the target temperature of 32degrees C. in less than 24 minutes.

LV Estimate Error (i.e., the difference between the estimated LVtemperature (TempLV) and the actual LV temperature (ActualTempLV)measured by the LV Control Probe) and IVC Error (i.e., the differencebetween the actual IVC temperature measured by the IVC probe and theactual LV temperature (ActualTempLV) measured by the LV Control Probe)were calculated for each animal at time points three (3) seconds beforeeach pump stop. Table 1 below shows the Mean estimated LV temperature,the Mean actual LV temperature, the Mean actual IVC temperature, Mean LVEstimate Error and Mean IVC Error of the seven (7) animals at each timepoint before pump stops 1 through 8. These values were obtained usingk1=0.002, L=0 and calculating k2 as per the formula referenced herein.Values for k2 ranged from 0.0115 to 0.003.

TABLE 1 LV err IVC err Mean Mean Mean Std. Std. LV est LV act IVC MeanDev Mean Dev Power 33.96 34.79 32.52 −0.8 1.1 −2.3 1.4 529.3 33.17 33.3230.61 −0.2 0.4 −2.4 1.4 518.4 32.01 32.10 29.62 −0.1 0.3 −2.3 1.4 440.631.99 31.91 30.64 0.1 0.2 −1.2 0.9 214.4 32.25 32.27 31.60 0.0 0.2 −0.70.7 195.8 32.68 32.69 32.48 0.0 0.2 −0.3 0.6 142.1 33.72 33.74 33.99 0.00.1 0.2 0.1 −54.3 34.23 34.51 34.15 0.0 0.7 0.3 1.5 −78.2

These data set forth in Table 1 are also shown graphically in FIG. 15.The LV Estimate Error data demonstrates that the estimated LVtemperature determined in accordance with this invention consistentlyprovided an accurate and reproducible estimate of actual LV temperature.The Mean LV Estimate Error was near zero for each of the time pointspreceding Pump Stops 2 through 8. The Mean LV Error for the time pointpreceding Pump Stop 1 was 0.8+/−1.1. However, that first estimated LVtemperature determination was made based solely on the factory pre-setK2 value and does not have the benefit of computed K2 values, as do thelater determinations preceding Pump Stops 2 through 8. As describedabove, in some embodiments of the system, the controller will beprogrammed not to display estimated LV temperature until the system hasperformed at least one prior pump stop with at least one priorcomputation of the K2 value.

The IVC Error data demonstrates that the actual IVC temperature, asmeasured by the IVC Probe, was substantially different from the actualLV temperature measured by the LV Probe at a number of time points. TheIVC Error was greater than the LV Estimate Error at each time point. Inthis study, the estimated LV Temperature for time points after the firstpump stop were accurate and reliable estimates of actual LV temperatureas measured by the LV Probe.

The endovascular temperature management system 10 described in variousembodiments herein is a high powered system, capable of rapidly coolinga patient.

In certain embodiments, the cassette/console is designed and configuredsuch that it is capable of delivering ≤4° C. working fluid or saline ata rate of ≥600 mL/min, at steady state, when up to 700 W of heat isadded to the working fluid or saline loop (e.g., heat added by thesubject's body).

In certain embodiments, the cassette/console is designed and configuredsuch that it is capable of delivering ≤4° C. working fluid or saline ata rate of 220+−20 mL/min, at steady state, when ≤70 W of heat is addedto the working fluid or saline loop (e.g., heat added by the subject'sbody).

In certain embodiments, the cassette/console is designed and configuredsuch that it is capable of delivering ≥42° C. working fluid or saline ata rate of >400 mL/min, at steady state, when up to 200 W of heat isremoved from the working fluid or saline loop.

In certain embodiments, the system (cassette, console, and catheter) isdesigned and configured such that it is capable of delivering greaterthan 400 Watts, or greater than or equal to 500 Watts, or greater thanor equal to 600 Watts of cooling power, e.g., with ≤4° C. working fluidor saline at a catheter pressure of about 60 PSI. In certainembodiments, the system may deliver from 500 to 700 W or 600 to 700 W ofcooling power or about 675 W of cooling power or greater than 700 W ofcooling power.

In certain embodiments, the system (cassette, console, and catheter) isdesigned and configured such that it is capable of delivering >than orequal to 50 W of warming power e.g., with >37° C. working fluid orsaline at a catheter pressure of about 40 PSI.

In certain embodiments, the system performance parameters were verifiedduring a bench test. The bench test included placing a catheter (whichis connected to a console/cassette assembly) in a rigid 22 mm ID tube,which simulates the average IVC (inferior vena cava) diameter, throughwhich water at a temperature of 37 degrees C. is flowing at a rate of2.5 liters per minute (simulating blood flow) over the catheter in adirection from the proximal end of the catheter to the distal end of thecatheter.

In certain embodiments, in maintenance and controlled rate warming, thesystem may control a stable patient's temperature, as measured byconsole, within about 0.3° C. of target when using a temperature sensoror probe on or in the catheter. During normal use and in the case of asudden saline loop blockage, the system shall regulate and limit workingfluid or saline pressure for catheters as follows: <20 C: 60 psinominal, 90 psi limit; >=20 C: 40 psi nominal, 70 psi limit; or 40 psinominal, 70 psi limit. The console working fluid pump and cassette shallbe capable of an output up to 600 mL/min at 70 psi. Saline or workingfluid pressure at the outlet of the saline pump may be measured, e.g.,over a range of 0-100 psi with an accuracy of ±5 psi over the range10-70 psi. The system may be used concurrently with a defibrillator,electro surgical unit or other device or during an MRI. The console andcassette together may be capable of delivering <8° C. saline, at a rateof 600 mL/min, within 5 minutes of turning on the console, when startingwith the system equilibrated to ambient temperature. The console andcassette together may be capable of changing the temperature from 4° C.to 40° C. within 10 minutes.

The estimated target temperature, estimated or calculated in accordancewith the embodiments described herein, provides feedback to the console,which in turn increases, decreases or maintains cooling/warming power ofthe system based on the feedback. The proximity of the temperaturesensor to the catheter may determine how accurately the sensor is ableto measure the patient temperature since the catheter power outputinfluences the measured temperature. The catheter power output is firsttransferred to the patient via the blood that comes into contact withthe catheter and it is slowly diffused across the patient via bloodflow, conduction and other processes. If the temperature sensor measuresthe blood temperature prior to the diffusion being complete, it mayindicate a lower than normal patient temperature. For the endovasculartemperature management system 10, described herein, the power output maybe large enough to cause such discrepancies between the actual patienttemperature and the temperature measured by the temperature sensor atthe end of the catheter. As a result, an estimation algorithm may beused in order to account for the power output of the catheterinfluencing the temperature measured by the sensor. The estimatedtemperature of a target location, e.g., the left ventricle, may be usedas a surrogate for body temperature or core body temperature.

In at least some cases where hypothermia is being induced fortherapeutic or prophylactic purposes, the speed with which the patientis cooled may be critical. For example, discussed above, at least inacute myocardial infarction (AMI) cases, lowering of the patient's corebody temperature to at least 35° C. prior to reperfusion of the ischemicmyocardium may have beneficial effects. In some hospitals reperfusionmay be accomplished as quickly as 30 to 60 minutes after the patient'sarrival at the facility. Thus, to effectively treat myocardialinfarction patients, it is desirable for the hypothermia system to haveenough power to cool the patient to a desired hypothermic temperaturebetween 32 to 34 degrees C. in less than 30 minutes, e.g., in about 25minutes or less or 20 minutes or less. However, such rapid cooling isnot without risks. Rapid cooling, if not properly controlled, may resultin overshoot of the intended hypothermic temperature in certain organsor areas of the body. For example, atrial fibrillation is believed to becommon when the heart is cooled to a temperature below 32 degrees C.

As demonstrated by the above-examples, the embodiment of the system 10used in the example does, indeed, have sufficient cooling power to coolthe body of an adult patient to a temperature of 32-34 degrees C. inless than 20 minutes. However, along with having the power needed forrapid cooling, this system 10 is additionally capable of safeguardingagainst overcooling or undercooling of the heart by monitoring andcontrolling the estimated cardiac temperature (i.e., estimated LVtemperature) rather than some other “core” body temperature taken at anextra-cardiac location (e.g., in the inferior vena cava, urinarybladder, rectum, etc.). By controlling the rate at which the patient'sblood is cooled based on feedback of an estimated cardiac temperature asopposed to some other “core” temperature measurement, the systemsdescribed in certain embodiments herein offer precise control of cardiaccooling to but not below a particular hypothermic temperature (e.g., 32degrees C.). This novel combination of therapeutic cooling power withfeedback control based on a monitored cardiac temperature estimate isparticularly useful in the rapid treatment of emergent disorders (e.g.,acute myocardial infarction) while protecting against inadvertentovercooling of the heart to an arrhythmogenic temperature.

At least some embodiments of the heat exchange catheter system 10 mayincorporate processors and user interfaces 38 programmed to provideadvanced control and informational features. FIGS. 16 through 22 showscreens that appear on the user interface 38 in connection with certainexamples of such advanced control and informational features inaccordance with the example set forth below.

FIG. 16 shows an example of a Modify Therapy Screen which may appear ona touch screen embodiment of the user interface 38 of the system 10 ofFIG. 1. This screen enables a user to modify the body temperaturecontrol protocol being used to treat a particular subject.

FIG. 17 shows an example of an Operation Screen which may appear on theuser interface of the system of FIG. 1. The Operation screen shows thecurrent status of therapy, including the following:

-   -   Patient Temp shows the patient's intravascular temperature,        which is based on the estimated temperature at the target        location derived as described herein.    -   Target Temp and Rate are chosen in the Modify Therapy Settings        screen (See Modify Therapy Settings Screen-FIG. 16).    -   Warming Effort and Cooling Effort shows the percentage of the        system's maximum warming or cooling capability currently being        expended.    -   The patient temperature graph shows the temperature over a 450        minute (7.5 hour) time span. The X-axis shows the time, in        minutes, and the Y-axis shows patient's temperature.    -   To open the Operation menu, press the menu arrow at the bottom        of the operation screen.

In this example, the user interface/screen may display the patienttemperature. The patient temperature output may be the estimated LVtemperature (TempLV). The estimated LV temperature represents or may beused as a surrogate for patient temperature or core body temperature.The estimated LV temperature may be calculated using any of the variousequations described herein. In other implementations, the estimatedtemperature of another organ or anatomical location, other than the LV,may be used as a surrogate for patient temperature or core bodytemperature, e.g., the femoral artery, aorta, kidney or liver.

Pressing the “MENU” icon at the bottom of the Operation Screen willinitiate a pop-up Menu display as shown in FIG. 17A. Pressing the“RESUME” icon on the Menu of FIG. 17A will cause the Menu to no longerbe visible on the screen and the display will return to the OperationScreen of FIG. 17. As shown, the Menu includes the followingicons/functionalities: Menu options are:

-   -   Re-Prime-Causes the system 10 to perform a re-priming procedure        in which the system is re-filled with saline solution and any        entrained air is purged from the system while no therapy is        provided. If therapy is paused, press Resume to resume therapy.    -   Modify—Pressing the Modify icon will bring up the Modify Therapy        screen shown in FIG. 16, thereby enabling the user to change the        patient's target temperature or rate of cooling/warming during        the treatment session.    -   Transport.—Causes the system 10 to pause a treatment session to        allow transport or movement of the subject. In certain        embodiments, the system may store all treatment session settings        and history so that, after the transport has been completed, the        user may elect to resume the ongoing treatment session at the        point where it has stopped prior to the transport without any        change in settings or stored history data.    -   End—Causes the treatment session to end.    -   History—.Pressing the History icon will bring up the History        screen shown in FIG. 18, thereby enabling the user to scroll        through a graphic display of the entire temperature history and        percent effort for the current treatment session. Pressing the +        or −icons on any screen where they appear will cause the display        to zoom in or out on a specific portion of the information        displayed on that screen (see example of zoom feature in FIGS.        19-20).    -   Settings—Pressing the Settings icon will bring up the Settings        Screen shown in FIG. 22.

FIG. 18 shows a History Screen which may appear on the user interface ofthe system of FIG. 1. This screen displays graphic display of thesubject body temperature history and percent effort for the currenttreatment session.

FIG. 19 shows a Patient Temperature Screen which may appear on the userinterface of the system of FIG. 1 This screen provides a graphic displayof subject body temperature and percent effort for the preceding onehour.

FIG. 20 shows an enlarged “zoom” view of a portion of the graphicdisplayed on the screen in FIG. 19 accessed by pressing the +icon.Pressing the −icon will cause the display to zoom out and resume thefull one hour display seen in FIG. 19.

FIG. 21 shows an Administration Screen which may appear on the userinterface of the system of FIG. 1. The Admin screen allows you to setthe default settings. The Admin screen includes the following:

-   -   Default Target Temp    -   Default Warming Rate. The rate at which the patient is warmed,        in degrees per hour.    -   Default screen brightness    -   Default Alarm Volume. To test the alarm volume, press the up and        down arrows.    -   Pump. Opens the pump head in case you want to bypass the End        therapy procedure and remove the cassette.    -   Default Pause Reminder Interval.    -   Temperature Units. Choose to view the temperature in degrees        Celsius or Fahrenheit.    -   Language    -   Set Date. Press to show a calendar and select the current date.    -   Local time. Set the time in 12 or 24 hour formats.

FIG. 22 shows a Settings Screen which may appear on the user interfaceof the system of FIG. 1 to allow operator adjustment of the indicatedsettings.

In certain embodiments, one or more of the systems described herein mayalso include one or more physiological alarms and/or technical alarms.The physiological alarms may appear next to the patient's temp on thedisplay screen, and may occur when the patient temperature exceeds thehigh or low patient temperature alarm value. Technical alarms may appearelsewhere on the display screen and may be triggered by console errorsor other events, e.g., probe or catheter disconnection, saline loopoverpressure, pump malfunction or open lid, and may be displayed bypriority. Any of the alarms may be audible. The system may also transmitdata, including patient and/or treatment data wirelessly, e.g., viaWifi, Bluetooth or other wireless connection. Data may also betransmitted via USB, Ethernet or wired connection. The system may beelectrically powered or battery powered.

Hypothermic Treatment to Deter Reperfusion Injury

FIG. 23 shows one example of a clinical protocol that may be used toeffect rapid hypothermia to deter reperfusion injury in a subjectsuffering from an ischemic event that may be treated in a manner thatcauses reperfusion or restoration of blood flow to the ischemic tissue.Non-limiting examples of such reperfursion procedures includeangioplasty, stenting, atherectomy, embolectomy, thrombectomy, insertionof a perfusion wire or other conduit to carry blood or oxygenated fluidthrough or past an obstruction, administration or a thrombolytic agent(e.g., streptokinase or tissue plasminogen activator), some types ofsurgical revascularization, etc. While reperfusion treatments mayrestore a flow of blood or other oxygenated fluid to the ischemictissue, they can also result in significant reperfusion injury whichcontributes to the amount of tissue that is ultimately infarcted orcaused to become necrotic due to the ischemic event. Reperfusion injuryis thought to occur in stages. Initially, the ischemia causes increasedpermeability of capillaries and arterioles. When reperfusion isaccomplished, the renewed pressure within those damaged capillaries andarterioles results in diffusion and filtration of fluid into theadjacent tissue. This causes chemical imbalances within the tissue thatgive rise to an inflammatory response. These events and possibly othersresult in post-reperfusion damage to the tissue that may be permanent.

As explained herein, the above-described heat exchange catheter system10 has the unique ability to cool an adult human subject's body to ahypothermic temperature below 34 degrees C., and preferably between 32degrees C. and 34 degrees C., in approximately 20 minutes. This rapidinduction of hypothermia allows caregivers to select an appropriate timeto perform the reperfusion procedure after the subjects body temperaturehas been lowered to the target temperature. Prior studies have indicatedthat if hypothermia below 35 degrees C. is effected prior toreperfursion, the severity of reperfursion injury, and hence the size orseverity of any permanent tissue infarction, is reduced. Applicant hasperformed a pilot study using the above-described protocol fordeterrence of reperfusion injury in human subjects presenting athospital emergency departments suffering from acute ST elevationmyocardial infarction (STEMI). In this pilot study, subjects wererandomized into hypothermia and non-hypothermia (control) groups.Subjects in the hypothermia group received standard anti-shiveringmedication and a heat exchange catheter was placed in the inferior venacava (IVC). A high power heat exchange catheter system was then used torapidly cool the body of each subject in the hypothermia group to atemperature below 34 degrees C. within <90 minutes of the subject'sarrival in the emergency department. Each subject then underwentpercutaneous coronary Intervention (PCI) resulting in reperfusion of theischemic myocardium. The subjects in the hypothermia group had a bodytemperatures at the time of reperfusion (i.e., measured at PCI wirecrossing) of 33.6+1.0 degrees C.

Following completion of the reperfusion procedure, hypothermia wasmaintained in each hypothermia group subject for a period of three hoursat a target temperature setting of 32 degrees C. Thereafter, thehypothermia group subjects were gradually rewarmed to a body temperatureof 36 degrees C. at a rate of 1 degrees C. per hour.

Four to six days after the event, each subject underwent cardiacmagnetic resonance imaging (cMR) and infarct size divided by leftventricular mass (IS/LVM) was determined. On average, subjects in thehypothermia group had a 7.1% absolute change in IS/LVM and approximatelya 30% relative reduction compared to the non-hypothermia controls. A 5%absolute change in IS/LVM is generally viewed as a good clinicaloutcome.

The results of this pilot study, when compared with previously reporteddata, suggests that 1) cooling of the subject's body temperature at afaster rate (i.e., made possible by using a high cooling power system)results in reduced infarct size measured as IS/LVM, 2) There appears tobe a dose-response relationship whereby lower body temperature at thetime of reperfusion correlates with greater protection againstreperfusion injury and, thus, smaller infarct size.

Accordingly, a method for reducing reperfusion injury in a human oranimal subject who undergoes a reperfusion procedure following anischemic event (e.g., myocardial infarction, acute coronary syndrome,stroke, infarction or ischemia of any metabolic tissue or organincluding but not limited to heart, lung, kidney, liver and brain) isprovided. In this method, the heat exchange catheter 12 is inserted intothe subject's vasculature and the system 10 is used to lower a bodytemperature of the subject to a temperature below 34 degrees C. andpreferably between 32 degrees C. and 34 degrees C. prior to reperfusion.The above described techniques for estimating body temperature at atarget location may be utilized in this method and the target locationmay be in or near the organ or tissue where the ischemia is occurring.For example, in a subject suffering from an evolving myocardialinfarction of myocardial ischemia, the system 10 may operate to lowerthe estimated cardiac temperature (LV Temperature) to the hypothermictemperature. Thereafter, caregivers may perform a reperfusion procedureat a selected time after the body temperature has been cooled to thetarget hypothermic temperature, thereby deterring reperfusion injuryand/or reducing the amount of tissue that ultimately becomes infarctedor necrotic.

It is to be appreciated that, in some applications or embodimentsdescribed herein, the intent may be to effect whole body cooling and/orwarming to control the patient temperature or core body temperature ofthe subject and, in those applications or embodiments, the estimatedtemperature at the target location may be used as an indication orsurrogate for the subject's core body temperature. In other applicationor embodiments, the intent may be to effect selective warming or coolingof a particular organ or area of the subject's body and, in thoseapplications or embodiments, the estimated temperature at the targetlocation may be used to effect precise control of the local temperatureof that particular organ or area of the subject's body even though,depending on where the heat exchange catheter(s) is/are positioned andhow the heat exchange catheter(s) is/are used, there may or may not alsobe incidental warming or cooling of the subject core body temperature.In the examples where estimated left ventricular temperature (TempLV) isused, such temperature has been determined to not only be an indicatorof local cardiac temperature but also a reliable indicator of orsurrogate for the subject's body temperature or core body temperature.

FIG. 24 is a diagram 100 relating to a system 10 wherein the controller36 is programmed to effect a combination of time-based reduced heatexchange period(s) 102, 108, and estimated temperature-based reducedheat exchange period(s) 104, 106. For example, the controller may beprogrammed to cause at least one time-based reduced heat exchange periodto occur based on one or more elapsed time period(s), 102, at least oneestimated temperature-based reduced heat exchange period to occur basedon difference(s) between the estimate of temperature at the targetlocation and the target temperature 104, at least one estimatedtemperature-based reduced heat exchange period to occur when theestimate of temperature at the target location becomes equal to thetarget temperature 106, and at least one time-based reduced heatexchange period to occur based on one or more elapsed time period(s)after the estimated temperature-based reduced heat exchange period thatoccurred when the estimate of temperature at the target location becameequal to the target temperature 108. As described above, during eachreduced heat exchange period, heat exchange between the heat exchangerand the subject's flowing blood is reduced or stopped such that, duringthe period of reduced heat exchange, the temperature sensor may sense atemperature at the sensing location without the effect of ongoing oractive cooling or warming of the blood by the heat exchanger. Forexample, in a system where a pump is used to circulate heat exchangefluid through an intravascular heat exchange catheter, the pump may beslowed or stopped causing a reduced heat exchange period where heatexchange between the heat exchanger and the subject's flowing blood isreduced compared to the amount of heat exchange that takes place whilethe pump is operating or actively circulating or pushing fluid throughthe heat exchange catheter. The temperature sensed by the sensor duringone or more of the reduced heat exchange periods is then used in analgorithm or formula or for revision of an algorithm or formula used forestimating or for calculation of the estimate or a running estimate oftemperature at the target location (e.g., calculation or recalculationof constant(s) or factor(s) used in the algorithms or formulas describedherein, e.g., K1 and/or K2) The controller may be configured tocontinuously calculate or estimate the temperature at the targetlocation during an entire or substantially entire patient treatment,e.g., during periods of reduced heat exchange as well as during periodswhen heat exchange is not reduced (e.g., while a heat exchange fluidpump is stopped or slowed and while the heat exchange fluid pump isoperating).

In the particular non-limiting example of FIG. 24, the subject's body isbeing cooled from an initial normothermic temperature (e.g., 37 degreesC.) to a hypothermic target temperature (e.g., whole body or local).After the heat exchanger and temperature sensor have been positioned inor on the body and the intended target temperature has been input to thecontroller, e.g., via a user interface or other input, cooling isinitiated and the controller 36 effects one or more initial time-basedreduced heat exchange period(s) 102 at certain time intervals, such asevery 60 to 120 seconds, for example every 90 seconds. When the estimateof temperature at the target location reaches a value that is X degrees(e.g., 1.5 degrees C.) above the target temperature, the controller 36will cause a temperature-based reduced heat exchange period 104 tooccur. Thereafter, when the estimate of temperature at the targetlocation becomes equal to the target temperature, the controller 36 willcause a temperature-based or target attainment-based reduced heatexchange period 106 to occur. After attainment of the targettemperature, the controller will effect post target attainment-basedreduced heat exchange periods to occur at time intervals (e.g., everyten minutes) or when certain changes in the estimate(s) or runningestimate of temperature at the target location occur.

It is to be further understood that the above-described example of FIG.24 is non-limiting. Other logic paths, logic permutations, skipping oraddition of steps or states, deviations, options, etc. are possible andmay be employed when the clinical situation and/or patient condition sowarrant. Also, although some of the examples described in thisapplication involve estimation of temperature at a target location thatis different or remote from the temperature sensing location and/or heatexchange location, in certain examples, the target location may be thesame or substantially the same as the temperature sensing locationand/or heat exchange location. In certain embodiments, the targetlocation may differ from or be the same as one or more of thetemperature sensing location and heat exchange location. Also, althoughsome of the examples described in this application involve estimation oftemperature at a target location in the left ventricle, it is to beappreciated that the target location may be anywhere in the body,including but not limited to in the inferior or superior vena cava, in acentral venous location such as the right atrium, or in the pulmonaryartery or other locations representative of whole body temperature(e.g., a core temperature) or at specific locations such as the leftventricle or in another organ or tissue of interest. In applicationswhere whole body warming or cooling is intended, the target locationmay, for example, be in a central venous location (e.g., in the rightatrium), the left ventricle, or a location for sensing the temperatureof mixed venous blood in the pulmonary artery if a pulmonary arterycatheter or other means exist for sensing pulmonary artery temperature.The estimate of the temperature at the target location may be used as anindicator of or surrogate for local temperature at the target locationand the system is useable to control temperature at the target locationwith or without incidental cooling or warming of the subject's core bodytemperature. The estimated temperature at the target location may beused as an indicator of or surrogate for the subject's core bodytemperature and the system is useable to control the subject's core bodytemperature.

It is to be further appreciated that, although the invention has beendescribed hereabove with reference to certain examples or embodiments ofthe invention, various additions, deletions, alterations andmodifications may be made to those described examples and embodimentswithout departing from the intended spirit and scope of the invention.For example, any elements, steps, members, components, compositions,reactants, parts or portions of one embodiment or example may beincorporated into or used with another embodiment or example, unlessotherwise specified or unless doing so would render that embodiment orexample unsuitable for its intended use. Also, where the steps of amethod or process have been described or listed in a particular order,the order of such steps may be changed unless otherwise specified orunless doing so would render the method or process unsuitable for itsintended purpose. Additionally, the elements, steps, members,components, compositions, reactants, parts or portions of any inventionor example described herein may optionally exist or be utilized in theabsence or substantial absence of any other element, step, member,component, composition, reactant, part or portion unless otherwisenoted. All reasonable additions, deletions, modifications andalterations are to be considered equivalents of the described examplesand embodiments and are to be included within the scope of the followingclaims.

1. A system for warming or cooling a subject to a target temperature,said system comprising: a heat exchanger configured to exchange heatwith the subject's flowing blood at a heat exchange location; atemperature sensor configured to sense the temperature of the subject'sblood at a temperature sensing location within the subject'svasculature; and controller which comprises memory and a processor;wherein: the controller is programmed to induce a plurality of periodsof reduced heat exchange between the heat exchanger and the subject'sflowing blood; the controller receives data representing sensed bloodtemperature during at least one of the plurality of reduced heatexchange periods; the controller is programmed to use said received datato provide an estimate of temperature at a target location in thesubject.
 2. A system according to claim 1 wherein the controller isprogrammed to cause at least one of the reduced heat exchange periods tooccur based on the estimate of temperature at the target location.
 3. Asystem according to claim 2 wherein the controller causes at least oneof the reduced heat exchange periods to occur based on the occurrence ofan event selected from: predetermined change in the estimate oftemperature at the target location; and the estimate of temperature atthe target location coming within a predetermined range of the targettemperature.
 4. (canceled)
 5. A system according to claim 1 wherein thecontroller is programmed to cause at least one of the reduced heatexchange periods to occur based on elapsed time and to cause at leastone of the reduced heat exchange periods to occur based on the estimateof temperature at the target location.
 6. A system according to claim 5wherein the controller is programmed to cause: at least one time-basedreduced heat exchange period to occur based on one or more elapsed timeperiod(s); and, thereafter, at least one estimated temperature-basedreduced heat exchange period to occur based on the estimate oftemperature at the target location.
 7. A system according to claim 6wherein said at least one estimated temperature-based reduced heatexchange period is caused to occur based on Ran the occurrence of anevent selected from: predetermined magnitude of change in the estimateof temperature at the target location; the estimate of temperature atthe target location coming within X degrees of the target temperature;and the estimate of temperature at the target location becomes equal tothe target temperature.
 8. (canceled)
 9. A system according to claim 1wherein the controller further comprises a user interface by which auser may input the target temperature.
 10. (canceled)
 11. A systemaccording to claim 6 wherein the controller is programmed to cause anestimated temperature-based reduced heat exchange period to occur whenthe estimate of temperature at the target location becomes equal to thetarget temperature and at least one time-based reduced heat exchangeperiod to occur based on one or more elapsed time period(s) aftercompletion of said estimated temperature-based reduced heat exchangeperiod.
 12. A system according to claim 11 wherein one or more timebased reduced heat exchange period(s) occurs at one more timed internalsafter the estimated temperature-based reduced heat exchange period thatoccurred when the estimate of temperature at the target location becameequal to the target temperature the target-attainment reduced beatexchange period.
 13. A system according to claim 3 wherein thecontroller is programmed to cause: at least one time-based reduced heatexchange period to occur based on one or more elapsed time period(s); atleast one estimated temperature-based reduced heat exchange period tooccur based on difference(s) between the estimate of temperature at thetarget location and the target temperature; at least one estimatedtemperature-based reduced heat exchange period to occur when theestimate of temperature at the target location becomes equal to thetarget temperature; and, at least one time-based reduced heat exchangeperiod to occur based on one or more elapsed time period(s) after theestimated temperature-based reduced heat exchange period that occurredwhen the estimate of temperature at the target location became equal tothe target temperature.
 14. (canceled)
 15. A system according to claim13 wherein an estimated temperature-based reduced heat exchange periodoccurs when the estimate of temperature at the target location becomeswithin X degrees of the target temperature.
 16. A system according toclaim 15 wherein X=1.5 degrees C.
 17. (canceled)
 18. A system accordingto claim 1 wherein the temperature sensing location and the targetlocation are different locations.
 19. A system according to claim 2wherein the temperature sensing location, and the target location aredifferent locations.
 20. A system according to claim 1 wherein thetarget location is within the left ventricle of the subject's heart orcentral venous location of the subject, the heat exchange location iswithin the subject's inferior vena cava or superior vena cava, and thetemperature sensing location is in the subject's vasculature downstreamor upstream of the heat exchange location.
 21. A system of claim 1wherein both the temperature sensing location and the target locationare the same.
 22. A system of claim 2 wherein both the temperaturesensing location and the target location are the same.
 23. A system ofclaim 1 wherein both the heat exchange location and the temperaturesensing location are in the subject's inferior vena cava and the targetlocation is in the subject's right atrium or left ventricle.
 24. Asystem of claim 1 wherein the controller adjusts the heat exchange powerof the heat exchanger.
 25. A system according to claim 1 wherein theheat exchanger is configured for circulation of a heat exchange fluidtherethrough and wherein the system further comprises a pump which pumpsheat exchange fluid through the heat exchanger and wherein thecontroller causes the reduced heat exchange periods to occur by stoppingor slowing the pump.
 26. A system according to claim 1, wherein thecontroller is programmed to use said received data to provide a runningestimate of temperature at the target location in the subject.
 27. Asystem according to claim 26 wherein the running estimate of temperatureat the target location is calculated continuously.
 28. A system forwarming or cooling a subject to a target temperature, said systemcomprising: a heat exchange catheter having a heat exchanger throughwhich a heat exchange fluid circulates, said heat exchange catheterbeing insertable into the subject's vasculature such that the heatexchanger exchanges heat with blood flowing through the subject'svasculature at a heat exchange location; a temperature sensor configuredto sense the temperature of the subject's blood at a temperature sensinglocation within the subject's vasculature; and a controller whichcomprises memory and a processor; wherein: the controller is programmedto alter the temperature and/or flow rate of the heat exchange fluid soas to induce a plurality of periods of reduced heat exchange between theheat, exchanger and the subject's flowing blood; the controller receivesdata representing sensed blood temperature during at east one of theplurality of reduced heat exchange periods; the controller, isprogrammed to use said received data to, provide an estimate oftemperature at a target location in the subject.
 29. A system accordingto claim 2$ wherein the controller is programmed to cause at least oneof the reduced heat exchange periods to occur based on the estimate oftemperature at the target location.
 30. (canceled)
 31. (canceled)
 32. Asystem according to claim 28, wherein the controller is programmed tocause at least one of the reduced heat exchange periods to occur basedon elapsed time and to cause at least One of the reduced heat exchangeperiods to occur based on the estimate of temperature at the targetlocation.
 33. (canceled)
 34. A system according to claim 28 wherein theheat exchanger is configured for circulation of a beat exchange fluid,therethrough and wherein the system further comprises a pump which pumpsheat exchange fluid through the heat exchanger and wherein thecontroller causes the reduced heat exchange periods to occur by stoppingor slowing the pump. 35.-56. (canceled)